This proposal describes the establishment of a model organism screening center (MOSC) for the Undiagnosed Diseases Network (UDN). The proposed MOSC will play a role in variant selection in close collaboration with the centers and sites of the UDN. The Leadership will obtain from the UDN a list of 300 candidate variants per year, and use independent genomic data available at Baylor College of Medicine (BCM) from rare disease cohorts to compare variants, human phenotypes and ultimately select 200 variants per year for experimentation. We will then assign variants (estimated 130 per year) conserved in Drosophila to the Drosophila Core at BCM. In the Drosophila Core, innovative technology will be used to tag proteins with GFP in the endogenous locus and examine expression pattern. These lines are to be generated by another large collaborative effort through the Drosophila Gene Disruption Project (GDP), saving cost for the MOSC. We will also use this technology to produce mutations that will be evaluated in a battery of phenotypic assays. This will guide experimental design and the generation of transgenics in Drosophila carrying human cDNAs. The 70 estimated variants per year assigned to the Zebrafish Core at the University of Oregon will be prioritized using existing expression and phenotypic data in fish and mice by analyzing the Human Phenotype Ontology annotations of the UDN patients and take advantage of the Zebrafish Core connection to the Zebrafish Informatics Network (ZFIN). The Zebrafish Core will then gathers existing mutations or generate new mutations with CRISPR/Cas9 and perform high throughput phenotypic analyses. The proposed MOSC also plans to share data with the UDN sites and centers every two months and to establish a website accessible to the entire UDN showing results and work in progress. No personal information, patient information or symptoms will be mentioned and we will only share it with investigators that are directly involved in the project. We also outline a plan for the Leadership to interact with the physicians for diagnostic o medically actionable data. Therefore the proposed center uses the most innovative technology in human genomics, Drosophila and zebrafish to provide diagnostic information for UDN patients.